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TASIGNA® (NILOTINIB) CAPSULES IMPORTANT SAFETY INFORMATION
WARNING: QT PROLONGATION AND SUDDEN DEATHS
- TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments
- Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome
- Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors
- Patients should avoid food 2 hours before and 1 hour after taking dose
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
WARNINGS AND PRECAUTIONS
Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.
TASIGNA prolongs the QT interval. ECGs should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.
Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
Sudden deaths have been reported in patients with CML treated with TASIGNA in clinical studies (n=5661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of TASIGNA suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
Elevated Serum Lipase
Caution is recommended in patients with a history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.
Serum bilirubin and hepatic transaminases
The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.
TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating TASIGNA and these electrolytes should be monitored periodically during therapy.
The concomitant use of QT-prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA.
Concomitant strong CYP3A4 inhibitors
The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.
Concomitant strong CYP3A4 inducers
The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should also refrain from taking St. John’s wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of TASIGNA when co-administered with such agents is unlikely to compensate for the loss of exposure. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9 and decrease the concentrations of drugs that are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein (Pgp). If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.
Drugs that affect gastric pH
Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TASIGNA is not recommended.
When the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of TASIGNA.
If necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of TASIGNA.
Food increases blood levels of TASIGNA. Patients should avoid food for at least 2 hours before and for at least 1 hour after the dose is taken.
Nilotinib exposure is increased in patients with impaired hepatic function.
Tumor Lysis Syndrome
Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell counts, and/or dehydration were present in most of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.
The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy.
Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
Use in Pregnancy
There are no adequate and well-controlled studies of TASIGNA in pregnant women. However, TASIGNA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do.
In patients with newly diagnosed Ph+ CML-CP
The most common (>10%) nonhematologic adverse drug reactions (ADRs) were rash, pruritus, headache, nausea, fatigue, and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, pain in extremity, dyspepsia and asthenia were observed less commonly (≤10% and >5%) and have been mild to moderate in severity, manageable, and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% and <1% of patients, respectively. Gastrointestinal hemorrhage was reported in 2.5% of patients.
The most common hematologic ADR (all grades) was myelosuppression, including thrombocytopenia (18 %), neutropenia (15%), and anemia (7%).
In patients with resistant or intolerant Ph+ CML-CP and CML-AP
In chronic phase patients, the most commonly reported nonhematologic ADRs (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious ADRs (≥1% and <10%) were thrombocytopenia, neutropenia, and anemia.
In accelerated phase patients, the most commonly reported nonhematologic ADRs (≥10%) were rash, pruritus, and fatigue. The common serious ADRs (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia.
DOSE ADJUSTMENTS OR MODIFICATIONS
TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors.
For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.
If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended and QT interval should be monitored. The following dose reductions should be considered:
Newly diagnosed Ph+ CML-CP
For patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe hepatic impairment (Child-Pugh Class C), an initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability should be considered.
Resistant or intolerant Ph+ CML-CP and CML-AP
For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability should be considered.
OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION
TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast-feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.
Click here for full Prescribing Information including Boxed WARNING.
TASIGNA (nilotinib) Capsules Indications
TASIGNA (nilotinib) is indicated for the treatment of newly diagnosed adult patients with Philadelphia
chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome.
TASIGNA is indicated for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates.
Important Safety Information for GLEEVEC® (imatinib mesylate)
- GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life threatening. Be advised to carefully investigate and provide appropriate management for unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. Severe edema and superficial edema were observed in 1.5% to 6% of CML patients. If severe fluid retention occurs, manage with diuretic therapy and withhold GLEEVEC until the event has resolved, and then resume depending on the initial severity of the event
- Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (eg, every 2-3 months). Dose reduction, treatment interruption, or in rare cases discontinuation of treatment may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations)
- Severe congestive heart failure and left ventricular dysfunction have been reported. Most patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac disease or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated
- Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed depending on the initial severity of the event
- When GLEEVEC is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended
- In the newly diagnosed CML trial, 1.8% of patients had hemorrhage (NCI Grades 3/4)
- In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cardiogenic shock and left ventricular dysfunction have been associated with HES cell degranulation upon initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC
- Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose, with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction
- Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients
- Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression from
- Fetal harm can occur when administered to a pregnant woman. Therefore, women of reproductive potential should be advised not to become pregnant while taking GLEEVEC tablets and to avoid breastfeeding while taking GLEEVEC because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use highly effective contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus
- Growth retardation has been reported in children and preadolescents receiving GLEEVEC. The long-term effects of prolonged treatment with GLEEVEC on growth in children are unknown; therefore, monitoring of growth in children taking GLEEVEC is recommended
- Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC
- Motor vehicle accidents involving patients receiving GLEEVEC have been reported. Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision, or somnolence during treatment with GLEEVEC. Caution should be recommended when driving a car or operating machinery
- In Ph+ CML trials,* severe (NCI Grades 3/4) lab abnormalities–including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (˜ 5%)–and severe (NCI Grades 3/4) adverse experiences, including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%), were reported among patients receiving GLEEVEC. Severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600 mg/d), and is more common in the elderly
- There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and gastrointestinal (GI) perforation
- GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. Johnís wort, and enzyme-inducing antiepileptic drugs, eg, phenytoin. The concomitant use of strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50%, and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions)
- Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose; future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment
Common Side Effects of GLEEVEC (imatinib mesylate)
- Almost all adult Ph+ CML patients who received GLEEVEC in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all grades) and those with rates greater than 45% were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), hemorrhage (29%-57%), musculoskeletal pain (38%-49%), fatigue (39%-48%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%)†
- Supportive care may help reduce the severity of some mild to moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary
- Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered at 400 mg twice a day. For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron
- GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation
- Patients should be instructed to take GLEEVEC exactly as prescribed and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose
*For more detailed study information, please see full Prescribing Information.
†Numbers indicate the range of percentages in 4 studies among adult patients, with newly diagnosed Ph+ CML, patients in blast crisis, accelerated phase, and in the chronic phase after failure of interferon-alpha therapy.
Click here for GLEEVEC full Prescribing Information.
GLEEVEC® (imatinib mesylate) tablets are indicated for:
- Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in the chronic phase
- Patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy